Burden and seasonality of primary and secondary symptomatic common cold coronavirus infections in Nicaraguan children

Abstract Background The current SARS‐CoV‐2 pandemic highlights the need for an increased understanding of coronavirus epidemiology. In a pediatric cohort in Nicaragua, we evaluate the seasonality and burden of common cold coronavirus (ccCoV) infection and evaluate likelihood of symptoms in reinfections. Methods Children presenting with symptoms of respiratory illness were tested for each of the four ccCoVs (NL63, 229E, OC43, and HKU1). Annual blood samples collected before ccCoV infection were tested for antibodies against each ccCoV. Seasonality was evaluated using wavelet and generalized additive model (GAM) analyses, and age–period effects were investigated using a Poisson model. We also evaluate the risk of symptom presentation between primary and secondary infections. Results In our cohort of 2576 children from 2011 to 2016, we observed 595 ccCoV infections and 107 cases of ccCoV‐associated lower respiratory infection (LRI). The overall incidence rate was 61.1 per 1000 person years (95% confidence interval (CI): 56.3, 66.2). Children under two had the highest incidence of ccCoV infections and associated LRI. ccCoV incidence rapidly decreases until about age 6. Each ccCoV circulated throughout the year and demonstrated annual periodicity. Peaks of NL63 typically occurred 3 months before 229E peaks and 6 months after OC43 peaks. Approximately 69% of symptomatic ccCoV infections were secondary infections. There was slightly lower risk (rate ratio (RR): 0.90, 95% CI: 0.83, 0.97) of LRI between secondary and primary ccCoV infections among participants under the age of 5. Conclusions ccCoV spreads annually among children with the greatest burden among ages 0–1. Reinfection is common; prior infection is associated with slight protection against LRI among the youngest children.

Younger children have higher rates of symptomatic and severe illness associated with ccCoV infection compared with older children and adults. 7,10,18 By age 3, most children have had their first ccCoV infection, and by age 6, children typically have antibodies against each of the four ccCoV types. 19,20 ccCoV infections occur repeatedly throughout life, suggesting the lack of long-lasting sterilizing immunity produced by natural infection. 21 Declining antibody levels following primary ccCoV infection may explain frequent ccCoV reinfection in children. 20 The clinical significance of primary versus secondary ccCoV infections in children is not well understood.
Many large ccCoV studies lack a well-defined study population and rely on reporting from hospitals, healthcare systems, and passive surveillance networks; these studies detect and report on the epidemiology of more severe ccCoV infections. 3,[6][7][8][9]11,13,14 Studies conducted in temperate locations report consistent annual seasonal peaks during winter months, similar to other common respiratory pathogens; ccCoV spread in other climates, however, does not appear to follow similar patterns and drivers of ccCoV seasonality remain unknown. 3,4,[7][8][9][10][11]22 Here, we describe the incidence and seasonality of symptomatic ccCoV infections and evaluate risk of symptom presentation of between primary and secondary ccCoV infections in a communitybased pediatric cohort in Managua, Nicaragua, from 2011 to 2016.

| METHODS
The Nicaraguan Pediatric Influenza Cohort (NPICS) is an ongoing prospective cohort study of children aged 0-14 years in Managua, Nicaragua, which has a tropical, urban environment. Previous work has detailed descriptions of study protocols. 23  impacted the seasonality of another, a cross-wavelet analysis was conducted. Using time-series data, wavelets can be used to identify periodic signals; cross-wavelet analysis allows us to evaluate the temporal relationship between two time series. [27][28][29] A generalized additive model was used to identify peak months for each group and type. To calculate incidence rates, a Poisson model was used. Crude rates and rates adjusted for period and for age were calculated; age was adjusted for using B-splines; age period provided better model fit than age cohort or period cohort. Crude and fitted incidence rates were displayed using hexamaps to visualize age-period-cohort (APC) trends. 30 To evaluate differences in symptom presentation between primary and secondary infections, symptom presentation risk was com- , and over the 6 years, there were six deaths ( Figure S1). Approximately 50% of participants were female. There were between 1436 and 1776 active participants each month. ( Figure S2).
Study personnel collected 9018 respiratory samples of which 8803 (97.6%) had sufficient sample remaining to test all four ccCoVs.
There was no clear season to ccCoV circulation, with cases presenting in every month of the study period ( Figure 1). NL63, 229E, and OC43 circulated annually throughout the study period. NL63 generally peaked in the last 6 months of the year, but there was no identified general peak month for the other ccCoVs (Figures 2 and S4).
Cross-wavelet analysis indicated that 229E peaks generally occur 3 months before NL63; we also found that NL63 and OC43 peaks occurred approximately 6 months apart from 2011 to 2013 but shifted to 3 months apart from 2014 to 2015 ( Figure S5).  (Figure 3). Incidence rates between males and females were similar (Table S1).
ccCoV-associated LRI incidence was 8.9 per 1000 person years (95% CI: 7.2, 11.0). LRI incidence was also the highest among the youngest participants, with all ccCoV-associated LRI incidence following a similar age pattern as symptomatic infection incidence (Figure 4). There was also no difference in ccCoV-associated LRI incidence by sex (Table S1).
Although it has been shown that people are repeatedly infected with ccCoVs, we hypothesized that the breadth of immunity would increase as children accumulate exposures to the same type, resulting in a decrease in the incidence of cases. Age-period-cohort analysis suggests that incidence declines sharply until around age 6 when incidence rates decline more slowly (Figures 5 and S6). At age 6, ccCoV incidence is less than 30% of infant ccCoV incidence. Symptomatic infections are relatively uncommon in individuals older than 10 years old. Periods that had higher incidence for a specific ccCoV (e.g., NL63 in 2013 and HKU1 in 2015) had higher incidence among all participants, including older children ( Figure S7). Compared with others,  [36][37][38][39][40][41][42] Consistent with other respiratory infections and previous research, younger children had a higher incidence of symptomatic ccCoV infections and ccCoV-associated LRI than older children, especially within the first 2 years of life. 3,7,[9][10][11][12]43 We note a clear pattern of rapidly decreasing incidence of symptomatic infection until about age 6 at which point nearly all infections are secondary. Additionally, ccCoV reinfection is very common among children 20 ; we found that by age 5, almost all symptomatic infections were secondary, not primary infections. Among those under 5 years of age, there was slightly lower risk of ccCoV-associated LRI for secondary infections compared with primary infections after adjusting for age. Similarly, frequent reinfection with SARS-CoV-2 has also been observed among children. 44 In a household transmission study, infection-induced immunity was not associated with protection against SARS-CoV-2 infection for children. 45 These findings suggest that although protection against ccCoV-associated LRI develops following a primary infection, protection against symptomatic infections wanes quicker early in life 20 but may build, lasting longer, over several exposures.
We also observed some years that had high ccCoV type-specific incidence rates across all ages. We expect that ccCoV type-specific genetic diversity, frequently detected among children, 46 may explain these high incidence years. Additionally, birth cohorts that experienced lower rates of symptomatic infections for a particular ccCoV type as infants had higher rates of symptomatic illness at age 1 compared with other cohorts; this was likely a result of both annual ccCoV spread and an absence of type-specific immunity acquired before the 1 year of age.
The main strength of this study is the size and duration of the prospective cohort. With over 9000 respiratory samples collected and over 7000 person years, we observed almost 600 ccCoV infections, exclusively among children. The 6 years of data provides sufficient power to evaluate seasonality statistically, identify annual periodicity, and evaluate the frequency of repeat ccCoV infections.
The consistent cohort age structure and limited loss-to-follow-up allowed us to identify age-period-cohort trends of symptomatic ccCoV illness.
We do note some limitations in this study. Respiratory swabs were only collected when a participant presented at the clinic with symptomatic illness, thus likely missing some mild cases and underestimating the true incidence of both ccCoV infections and the frequency of reinfections in the population. However, testing participants' blood samples F I G U R E 4 Common cold coronavirus (ccCoV)-associated lower respiratory infection incidence rates by age and type. Incidence rates (per 1000 person years) of PCR+ ccCoV-associated lower respiratory infections (LRI) for all ccCoV infections and by type using 1-year age groups. Shaded area represents 95% confidence intervals.